Christine McDonald

Each year, 3.3 million Americans are diagnosed with non‐melanoma skin cancers (NMSC) and an additional 40 million individuals undergo treatment of precancerous actinic keratosis lesions. The most effective treatments of NMSC (surgical excision and Mohs surgery) are invasive, expensive and require specialised training. More readily accessible topical therapies currently are 5‐fluorouracil (a chemotherapeutic agent) and imiquimod (an immune modulator), but these can have significant side effects which limit their efficacy. Therefore, more effective and accessible treatments are needed for non‐melanoma cancers and precancers. Our previous work demonstrated that the small molecule N‐phosphonacetyl‐L‐aspartate (PALA) both inhibits pyrimidine nucleotide synthesis and activates pattern recognition receptor nucleotide‐binding oligomerization domain 2. We propose that topical application of PALA would be an effective NMSC therapy, by combining the chemotherapeutic and immune modulatory features of 5‐fluorouracil and imiquimod. Daily topical application of PALA to mouse skin was well tolerated and resulted in less irritation, fewer histopathological changes, and less inflammation than caused by either 5‐fluorouracil or imiquimod. In an ultraviolet light‐induced NMSC mouse model, topical PALA treatment substantially reduced the numbers, areas and grades of tumours, compared to vehicle controls. This anti‐neoplastic activity was associated with increased expression of the antimicrobial peptide cathelicidin and increased recruitment of CD8 + T cells and F4/80 + macrophages to the tumours, demonstrating both immunomodulatory and anti‐proliferative effects. These findings indicate that topical PALA is an excellent candidate as an effective alternative to current standard‐of‐care NMSC therapies.